tbuckley/cabot-search huggingface dataset:
Nivolumab, Brentuximab Vedotin, +/- Bendamustine For R/R Hodgkin Lymphoma in Children, Adolescents, and Young Adults
Authors: Paul Harker-Murray, Christine Mauz-Körholz, Thierry M Leblanc, Maurizio Mascarin, Gérard Michel, Stacy Cooper, Auke Beishuizen, Kasey J. Leger, Loredana Amoroso, Salvatore Buffardi, Charlotte Rigaud, Bradford S. Hoppe, Julie M Lisano, Stephen Francis, Mariana Sacchi, Peter D. Cole, Richard A. Drachtman, Kara M. Kelly, Stephen Daw
Journal: Blood (2022)

Children, adolescents, and young adults (CAYA) with relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) without complete metabolic response (CMR) before autologous hematopoietic cell transplantation (auto-HCT) have poor survival outcomes. CheckMate 744, a phase 2 study for CAYA (aged 5-30 years) with R/R cHL, evaluated a risk-stratified, response-adapted approach with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response. Risk stratification was primarily based on time to relapse, prior treatment, and presence of B symptoms. We present the primary analysis of the standard-risk cohort. Data from the low-risk cohort are reported separately. Patients received 4 induction cycles with nivolumab plus BV; those without CMR (Deauville score >3, Lugano 2014) received BV plus bendamustine intensification. Patients with CMR after induction or intensification proceeded to consolidation (high-dose chemotherapy/auto-HCT per protocol). Primary end point was CMR any time before consolidation. Forty-four patients were treated. Median age was 16 years. At a minimum follow-up of 15.6 months, 43 patients received 4 induction cycles (1 discontinued), 11 of whom received intensification; 32 proceeded to consolidation. CMR rate was 59% after induction with nivolumab plus BV and 94% any time before consolidation (nivolumab plus BV ± BV plus bendamustine). One-year progression-free survival rate was 91%. During induction, 18% of patients experienced grade 3/4 treatment-related adverse events. This risk-stratified, response-adapted salvage strategy had high CMR rates with limited toxicities in CAYA with R/R cHL. Most patients did not require additional chemotherapy (bendamustine intensification). Additional follow-up is needed to confirm durability of disease control. This trial was registered at www.clinicaltrials.gov as #NCT02927769.
Targeting of colorectal cancer organoids with zoledronic acid conjugated to the anti-EGFR antibody cetuximab
Authors: Roberto Benelli, Delfina Costa, Laura Salvini, Samuele Tardito, Francesca Tosetti, Federico Villa, Maria Raffaella Zocchi, Alessandro Poggi
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Antibody-drug conjugates (ADC) are essential therapeutic options to treat solid and hematological cancers. The anti-epidermal growth factor-receptor (EGFR) antibody cetuximab (Cet) is used for the therapy of colorectal carcinoma (CRC). Anti-CRC Vδ2 cytolytic T lymphocytes can be elicited by the priming of tumor cells with the aminobisphosphonate zoledronic acid (ZA) and consequent presentation of isopentenyl pyrophosphates through butyrophilin (BTN) family members such as BTN3A1 and BTN2A1. A major drawback that impairs the targeting of ZA to CRC is the bone tropism of aminobisphosphonates. Methods The phosphoric group of ZA was linked to free amino groups of Cet in the presence of imidazole following the labeling of phosphoric groups of DNA to amino groups of proteins. The generation of Cet-ZA ADC was confirmed by matrix assisted laser desorption ionization mass spectrometry and inductively coupled plasma-mass spectrometry analysis. Thirteen CRC organoids were obtained with a chemically defined serum-free medium in Geltrex domes. Proliferation and activation of cytolytic activity against CRC organoids by Vδ2 T cells was detected with flow cytometry, crystal violet and cytotoxic probe assays and image analysis. Immunohistochemistry and quantification of BTN3A1 or BTN2A1 expression and the number of tumor infiltrating Vδ2 T cells in CRC were performed by automatic immunostaining, whole slide scanning and computerized analysis of digital pathology imaging. Results The novel ADC Cet-ZA was generated with a drug antibody ratio of 4.3 and displayed a reactivity similar to the unconjugated antibody. More importantly, patient-derived CRC organoids, or CRC tumor cell suspensions, could trigger the expansion of Vδ2 T cells from peripheral blood and tumor infiltrating lymphocytes when primed with Cet-ZA. Furthermore, Cet-ZA triggered Vδ2 T cell-mediated killing of CRC organoids. The expression of BTN3A1 and BTN2A1 was detected not only in CRC organoids but also in CRC specimens, together with a considerable amount of tumor infiltrating Vδ2 T cells. Conclusions These findings are proof of concept that the Cet-ZA ADC can be used to target specifically CRC organoids and may suggest a new experimental approach to deliver aminobisphosphonates to EGFR + solid tumors.
Induction of T-helper-17-cell-mediated anti-tumour immunity by pathogen-mimicking polymer nanoparticles
Authors: Sejin Son, Jutaek Nam, April S. Kim, Jinsung Ahn, Kyung Soo Park, May Thazin Phoo, Brett Sherren, Weiping Zou, Soo-Hong Lee, Omid C. Farokhzad, Jinjun Shi, James J. Moon
Journal: Nature Biomedical Engineering (2022)
Busting the myth of methotrexate chronic hepatotoxicity
Authors: Vincent Di Martino, Delphine Weil Verhoeven, Frank Verhoeven, François Aubin, Jérome Avouac, Lucine Vuitton, Frédéric Lioté, Thierry Thévenot, Daniel Wendling
Journal: Nature Reviews Rheumatology (2022)
Modification of PLAC8 by UFM1 affects tumorous proliferation and immune response by impacting PD-L1 levels in triple-negative breast cancer
Authors: Misha Mao, Yongxia Chen, Jingjing Yang, Yifan Cheng, Ling Xu, Feiyang Ji, Jichun Zhou, Xun Zhang, Zhaoqing Li, Cong Chen, Siwei Ju, Jiahang Zhang, Linbo Wang
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Triple-negative breast cancer is characterized by a poor prognosis and lack of targeted treatments, and thus, new targeting markers and therapeutic strategies are urgently needed. We previously indicated that PLAC8 promotes tumorigenesis and exerts multidrug resistance in breast cancer. Therefore, we aimed to characterize the PLAC8-regulated network in triple-negative breast cancer. Methods We measured the levels of PLAC8 in breast cancer cell lines and found that PLAC8 is post-translationally modified by ubiquitin-fold modifier 1 (UFM1). Then, we revealed a new regulatory system of PD-L1 by PLAC8 in triple-negative breast cancer. We also tested the molecular functions of PLAC8 in triple-negative breast cancer cell lines and measured the expression of PLAC8 and PD-L1 in breast cancer tissues. Results PLAC8 was generally highly expressed in triple-negative breast cancer and could be modified by UFM1, which maintains PLAC8 protein stability. Moreover, PLAC8 could promote cancer cell proliferation and affect the immune response by regulating the level of PD-L1 ubiquitination. Additionally, among patients with breast cancer, the expression of PLAC8 was higher in triple-negative breast cancer than in non-triple-negative breast cancer and positively correlated with the level of PD-L1. Conclusions Our current study discoveries a new PLAC8-regulated network in triple-negative breast cancer and provides corresponding guidance for the clinical diagnosis and immunotherapy of triple-negative breast cancer.
Warning About Xylazine, a Veterinary Sedative Found in Illicit Drugs
Authors: Rita Rubin
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Design of Recombinant Spider Silk Proteins for Cell Type Specific Binding
Authors: Vanessa Tanja Trossmann, Thomas Scheibel
Journal: Advanced Healthcare Materials (2022)

Cytophilic (cell-adhesive) materials are very important for tissue engineering and regenerative medicine. However, for engineering hierarchically organized tissue structures comprising different cell types, cell-specific attachment and guidance are decisive. In this context, materials made of recombinant spider silk proteins are promising scaffolds, since they exhibit high biocompatibility, biodegradability, and the underlying proteins can be genetically functionalized. Here, previously established spider silk variants based on the engineered Araneus diadematus fibroin 4 (eADF4(C16)) are genetically modified with cell adhesive peptide sequences from extracellular matrix proteins, including IKVAV, YIGSR, QHREDGS, and KGD. Interestingly, eADF4(C16)-KGD as one of 18 tested variants is cell-selective for C2C12 mouse myoblasts, one out of 11 tested cell lines. Co-culturing with B50 rat neuronal cells confirms the cell-specificity of eADF4(C16)-KGD material surfaces for C2C12 mouse myoblast adhesion.
Remote Ischemic Conditioning vs Usual Care and Neurologic Function in Acute Moderate Ischemic Stroke—Reply
Authors: Yu Cui, Hui-Sheng Chen
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Senescent cell population with ZEB1 transcription factor as its main regulator promotes osteoarthritis in cartilage and meniscus
Authors: Hannah Swahn, Kun Li, Tomas Duffy, Merissa Olmer, Darryl D D'Lima, Tony S Mondala, Padmaja Natarajan, Steven R Head, Martin K Lotz
Journal: Annals of the Rheumatic Diseases (2022)

Objectives Single-cell level analysis of articular cartilage and meniscus tissues from human healthy and osteoarthritis (OA) knees. Methods Single-cell RNA sequencing (scRNA-seq) analyses were performed on articular cartilage and meniscus tissues from healthy (n=6, n=7) and OA (n=6, n=6) knees. Expression of genes of interest was validated using immunohistochemistry and RNA-seq and function was analysed by gene overexpression and depletion. Results scRNA-seq analyses of human knee articular cartilage (70 972 cells) and meniscus (78 017 cells) identified a pathogenic subset that is shared between both tissues. This cell population is expanded in OA and has strong OA and senescence gene signatures. Further, this subset has critical roles in extracellular matrix (ECM) and tenascin signalling and is the dominant sender of signals to all other cartilage and meniscus clusters and a receiver of TGFβ signalling. Fibroblast activating protein (FAP) is also a dysregulated gene in this cluster and promotes ECM degradation. Regulons that are controlled by transcription factor ZEB1 are shared between the pathogenic subset in articular cartilage and meniscus. In meniscus and cartilage cells, FAP and ZEB1 promote expression of genes that contribute to OA pathogenesis, including senescence. Conclusions These single-cell studies identified a senescent pathogenic cell cluster that is present in cartilage and meniscus and has FAP and ZEB1 as main regulators which are novel and promising therapeutic targets for OA-associated pathways in both tissues.
Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular carcinoma
Authors: Rui-Qi Wu, Xiang-Ming Lao, Dong-Ping Chen, Hongqiang Qin, Ming Mu, Wen-Jie Cao, Jia Deng, Chao-Chao Wan, Wan-Yu Zhan, Jun-Cheng Wang, Li Xu, Min-Shan Chen, Qiang Gao, Limin Zheng, Yuan Wei, Dong-Ming Kuang
Journal: Immunity (2022)
Proximity proteomics identifies septins and PAK2 as decisive regulators of actomyosin-mediated expulsion of von Willebrand factor
Authors: Sammy El-Mansi, Christopher L. Robinson, Katja B. Kostelnik, Jessica J. McCormack, Tom P. Mitchell, Damián Lobato-Márquez, Vinothini Rajeeve, Pedro Cutillas, Daniel F. Cutler, Serge Mostowy, Thomas D. Nightingale
Journal: Blood (2022)

In response to tissue injury, within seconds the ultra-large glycoprotein von Willebrand factor (VWF) is released from endothelial storage organelles (Weibel-Palade bodies) into the lumen of the blood vasculature, where it leads to the recruitment of platelets. The marked size of VWF multimers represents an unprecedented burden on the secretory machinery of endothelial cells (ECs). ECs have evolved mechanisms to overcome this, most notably an actomyosin ring that forms, contracts, and squeezes out its unwieldy cargo. Inhibiting the formation or function of these structures represents a novel therapeutic target for thrombotic pathologies, although characterizing proteins associated with such a dynamic process has been challenging. We have combined APEX2 proximity labeling with an innovative dual loss-of-function screen to identify proteins associated with actomyosin ring function. We show that p21 activated kinase 2 (PAK2) recruits septin hetero-oligomers, a molecular interaction that forms a ring around exocytic sites. This cascade of events controls actomyosin ring function, aiding efficient exocytic release. Genetic or pharmacological inhibition of PAK2 or septins led to inefficient release of VWF and a failure to form platelet-catching strings. This new molecular mechanism offers additional therapeutic targets for the control of thrombotic disease and is highly relevant to other secretory systems that employ exocytic actomyosin machinery.
Activated B cells suppress T-cell function through metabolic competition
Authors: Nobuhiko Imahashi, Rafet Basar, Yuefan Huang, Fang Wang, Natalia Baran, Pinaki Prosad Banerjee, Junjun Lu, Ana Karen Nunez Cortes, Nadima Uprety, Emily Ensley, Luis Muniz-Feliciano, Tamara J Laskowski, Judy S Moyes, May Daher, Mayela Mendt, Lucila N Kerbauy, Mayra Shanley, Li Li, Francesca Lorraine Wei Inng Lim, Hila Shaim, Ye Li, Marina Konopleva, Michael Green, Jennifer Wargo, Elizabeth J Shpall, Ken Chen, Katayoun Rezvani
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background B cells play a pivotal role in regulating the immune response. The induction of B cell-mediated immunosuppressive function requires B cell activating signals. However, the mechanisms by which activated B cells mediate T-cell suppression are not fully understood. Methods We investigated the potential contribution of metabolic activity of activated B cells to T-cell suppression by performing in vitro experiments and by analyzing clinical samples using mass cytometry and single-cell RNA sequencing. Results Here we show that following activation, B cells acquire an immunoregulatory phenotype and promote T-cell suppression by metabolic competition. Activated B cells induced hypoxia in T cells in a cell–cell contact dependent manner by consuming more oxygen via an increase in their oxidative phosphorylation (OXPHOS). Moreover, activated B cells deprived T cells of glucose and produced lactic acid through their high glycolytic activity. Activated B cells thus inhibited the mammalian target of rapamycin pathway in T cells, resulting in suppression of T-cell cytokine production and proliferation. Finally, we confirmed the presence of tumor-associated B cells with high glycolytic and OXPHOS activities in patients with melanoma, associated with poor response to immune checkpoint blockade therapy. Conclusions We have revealed for the first time the immunomodulatory effects of the metabolic activity of activated B cells and their possible role in suppressing antitumor T-cell responses. These findings add novel insights into immunometabolism and have important implications for cancer immunotherapy.
Prevention of acute GVHD using an orthogonal IL-2/IL-2Rβ system to selectively expand regulatory T cells in vivo
Authors: Teresa L. Ramos, Sara Bolivar-Wagers, Sujeong Jin, Govindarajan Thangavelu, Federico Simonetta, Po-Yu Lin, Toshihito Hirai, Asim Saha, Brent Koehn, Leon L. Su, Lora K. Picton, Jeanette Baker, Juliane K. Lohmeyer, Megan Riddle, Cindy Eide, Jakub Tolar, Angela Panoskaltsis-Mortari, John E. Wagner, K. Christopher Garcia, Robert S. Negrin, Bruce R. Blazar
Journal: Blood (2022)
Oxidative DNA damage in reconstituting T cells is associated with relapse and inferior survival after allo-SCT
Authors: F. Karl, C. Liang, R. Böttcher-Loschinski, A. Stoll, C. Flamann, S. Richter, C. Lischer, S. Völkl, B. Jacobs, M. Böttcher, R. Jitschin, H. Bruns, T. Fischer, E. Holler, W. Rösler, T. Dandekar, A. Mackensen, D. Mougiakakos
Journal: Blood (2023)
Universal prevention through a digital health platform reduces injury incidence in youth athletics (track and field): a cluster randomised controlled trial
Authors: Jenny Jacobsson, Jan Kowalski, Toomas Timpka, Per-Olof Hansson, Armin Spreco, Orjan Dahlstrom
Journal: British Journal of Sports Medicine (2022)

Objectives To examine whether universal prevention via a digital health platform can reduce the injury incidence in athletics athletes aged 12–15 years and if club size had an influence on the effect of the intervention. Methods This was a cluster randomised trial where young athletics athletes were randomised through their club following stratification by club size into intervention (11 clubs; 56 athletes) and control (10 clubs; 79 athletes) groups. The primary endpoint was time from baseline to the first self-reported injury. Intervention group parents and coaches were given access to a website with health information adapted to adolescent athletes and were encouraged to log in and explore its content during 16 weeks. The control group continued training as normal. Training exposure and injury data were self-reported by youths/parents every second week, that is, eight times. The primary endpoint data were analysed using the log-rank test. Cox proportional hazards regression was used to analyse the second study aim with intervention status and club size included in the explanatory models. Results The proportion of completed training reports was 85% (n=382) in the intervention group and 86% (n=545) in the control group. The injury incidence was significantly lower (HR=0.62; χ 2 =3.865; p=0.049) in the intervention group. The median time to first injury was 16 weeks in the intervention group and 8 weeks in the control group. An interaction effect between the intervention and stratification factor was observed with a difference in injury risk between athletes in the large clubs in the intervention group versus their peers in the control group (HR 0.491 (95% CI 0.242 to 0.998); p=0.049). Conclusions A protective effect against injury through universal access to health information adapted for adolescent athletes was observed in youth athletics athletes. The efficacy of the intervention was stronger in large clubs. Trial registration number NCT03459313 .
Piezo2 channels expressed by colon-innervating TRPV1-lineage neurons mediate visceral mechanical hypersensitivity
Authors: Zili Xie, Jing Feng, Timothy J. Hibberd, Bao Nan Chen, Yonghui Zhao, Kaikai Zang, Xueming Hu, Xingliang Yang, Lvyi Chen, Simon J. Brookes, Nick J. Spencer, Hongzhen Hu
Journal: Neuron (2022)
The clinical relevance of detectable plasma iron species in iron overload states and subsequent to intravenous iron‐carbohydrate administration
Authors: Maciej W. Garbowski, Ioav Cabantchik, Chaim Hershko, Robert Hider, John B. Porter
Journal: American Journal of Hematology (2022)

Many disorders of iron homeostasis (e.g., iron overload) are associated with the dynamic kinetic profiles of multiple non-transferrin bound iron (NTBI) species, chronic exposure to which is associated with deleterious end-organ effects. Here we discuss the chemical nature of NTBI species, challenges with measuring NTBI in plasma, and the clinical relevance of NTBI exposure based on source (iron overload disorder vs. intravenous iron-carbohydrate complex administration). NTBI is not a single entity but consists of multiple, often poorly characterized species, some of which are kinetically non-exchangeable while others are relatively exchangeable. Prolonged presence of plasma NTBI is associated with excessive tissue iron accumulation in susceptible tissues, with consequences, such as endocrinopathy and heart failure. In contrast, intravenous iron-carbohydrate nanomedicines administration leads only to transient NTBI appearance and lacks evidence for association with adverse clinical outcomes. Assays to measure plasma NTBI are typically technically complex and remain chiefly a research tool. There have been two general approaches to estimating NTBI: capture assays and redox-activity assays. Early assays could not avoid capturing some iron from transferrin, thus overestimating NTBI. By contrast, some later assays may have promoted the donation of NTBI species to transferrin during the assay procedure, potentially underestimating NTBI levels. The levels of transferrin saturation at which NTBI species have been detectable have varied between different methodologies and between patient populations studied.